Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][O:16]1)[N:10]=[C:9]2[C:21]1[O:22][C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[CH:25]=1)=[O:5])C.O1CCCC1.[OH-].[Na+].Cl>O.CO>[O:22]1[C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[CH:25]=[C:21]1[C:9]1[C:8]2[C:12](=[CH:13][CH:14]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=2)[N:11]([CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)[N:10]=1
Reactant: CCOC(=O)c1ccc2c(c1)c(-c1cc3ccccc3o1)nn2C1CCCCO1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc2c(c1)c(-c1cc3ccccc3o1)nn2C1CCCCO1
Temperature: 65 °C
Yield: 80.5 %

Procedure:
To a solution of ethyl-3-benzo[d]furan-2-yl-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carboxylate (500 mg, 1.2 mmol) in a solution of tetrahydrofuran, methanol, and water (2:1:1) (4 mL) was added sodium hydroxide (200 mg, 5 mmol). The reaction was allowed to reflux overnight at 65° C. The solution was neutralized with 1 N HCl and extracted with ethyl acetate to yield the title compound (350 mg, 40% yield). ES-MS (m/z) 363 [M+1]+.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([C:11]([OH:13])=O)[CH2:3][CH2:2]1.[CH2:14]([N:16]1[CH:20]=[C:19]([CH2:21][NH:22][C:23]2[CH:28]=[CH:27][C:26]([CH:29]([CH3:31])[CH3:30])=[CH:25][CH:24]=2)[CH:18]=[N:17]1)[CH3:15]>>[CH2:14]([N:16]1[CH:20]=[C:19]([CH2:21][N:22]([C:23]2[CH:24]=[CH:25][C:26]([CH:29]([CH3:30])[CH3:31])=[CH:27][CH:28]=2)[C:11]([CH:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[O:1][CH2:2][CH2:3]2)=[O:13])[CH:18]=[N:17]1)[CH3:15]
Reactant: O=C(O)C1CCOc2ccccc21
Reactant: CCn1cc(CNc2ccc(C(C)C)cc2)cn1
Product: CCn1cc(CN(C(=O)C2CCOc3ccccc32)c2ccc(C(C)C)cc2)cn1
Yield: 85 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using chroman-4-carboxylic acid (0.27 g) and [(1-ethylpyrazol-4-yl)methyl](4-isopropylphenyl)amine (0.37 g) as starting materials, N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)chroman-4-carboxamide (0.52 g) was obtained.
Reaction SMILES: [C:1]1([S:7][CH2:8][C@@H:9]([C:11]([OH:13])=[O:12])[NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:14]([Cl:17])(=O)C>CO>[ClH:17].[CH3:14][O:12][C:11](=[O:13])[C@@H:9]([NH2:10])[CH2:8][S:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)Cl
Reactant: N[C@@H](CSc1ccccc1)C(=O)O
Solvent: CO
Product: COC(=O)[C@@H](N)CSc1ccccc1
Product: Cl
Yield: 60.5 %

Procedure:
To a solution of S-phenyl-L-cysteine (5.0 g, 25.4 mmol) in methanol (50 ml) was added acetylchloride (2.7 ml, 38 mmol) and the mixture was refluxed overnight. The solvent was evaporated and the residue was recrystallised from ethyl acetate/methanol (3:1) to yield a white solid (3.81 g, 61%). MS (ISP): 211.9 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[C:4]([F:22])[CH:3]=1.[CH:23]1([CH2:29][N:30]=[C:31]=[O:32])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.C(N(CC)CC)C>C(Cl)Cl>[CH:23]1([CH2:29][NH:30][C:31](=[O:32])[O:8][C:7]2[CH:6]=[C:5]([N:9]3[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:18])([F:17])[F:19])[N:11]([CH3:20])[C:10]3=[O:21])[C:4]([F:22])=[CH:3][C:2]=2[Cl:1])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: O=C=NCC1CCCCC1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(O)c(Cl)cc2F)c1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(OC(=O)NCC3CCCCC3)c(Cl)cc2F)c1=O

Procedure:
using 3-(4-chloro-2-fluoro-5-hydroxyphenyl)-1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione with cyclohexylmethyl isocyanate and triethylamine in methylene chloride there is obtained 2-chloro-5-[3,6-dihydro-2,6-dioxo-3-methyl-4-trifluoromethyl-1(2H) -pyrimidinyl]-4-fluorophenyl cyclohexylmethylcarbamate, m.p. 132°-135° C.;
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=O.ClC(OCC)=O.[CH2:24]([NH2:27])[CH2:25][NH2:26].Cl>C(Cl)(Cl)Cl>[ClH:8].[NH2:26][CH2:25][CH2:24][NH:27][C:11](=[O:13])[C:10]1[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=1[Cl:8]
Reactant: O=C(O)c1ccccc1Cl
Reactant: NCCN
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: NCCNC(=O)c1ccccc1Cl
Temperature: 0 °C
Yield: 108.9 %

Procedure:
22.1 ml (0.16 mol) of triethylamine are added dropwise at 10° to a suspension of 23.5 g (0.15 mol) of 2-chlorobenzoic acid in 200 ml of chloroform. 14.8 ml (0.155 mol) of ethyl chloroformate are then added dropwise at the same temperature. After completion of the addition (1 hour), the mixture is poured on to ice/water. The chloroform phase is separated, dried over magnesium sulfate and gently concentrated to about 60 ml. The thus-obtained solution is added dropwise at 10° to a solution of 40.1 ml (0.6 mol) of ethylenediamine in 400 ml of chloroform. After completion of the addition, the difficulty soluble neutral constituents are filtered off, the filtrate is concentrated and excess ethylenediamine is removed in a high vacuum. The residue obtained (31.5 g) is converted into the hydrochloride which is purified by recrystallization from ethanol/ether. There are obtained 19.2 g of N-(2-aminoethyl)-2-chlorobenzamide hydrochloride (see Example 6 of German Offenlegungsschrift 2.362.568), m.p. 155°-158°. An analytically pure sample melts at 159°-161°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH:4]([C:9]1[CH:10]=[C:11]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:12]=[C:13]([OH:15])[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7].[F:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[C:32]([F:35])[C:33]=1[F:34]>>[CH3:1][O:2][C:3](=[O:26])[CH:4]([C:9]1[CH:10]=[C:11]([C:16]2[CH:17]=[CH:18][C:19]([C:22]([F:23])([F:25])[F:24])=[CH:20][CH:21]=2)[CH:12]=[C:13]([O:15][C:30]2[CH:29]=[C:28]([F:27])[C:33]([F:34])=[C:32]([F:35])[CH:31]=2)[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)C(CC(C)C)c1cc(O)cc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: OB(O)c1cc(F)c(F)c(F)c1
Product: COC(=O)C(CC(C)C)c1cc(Oc2cc(F)c(F)c(F)c2)cc(-c2ccc(C(F)(F)F)cc2)c1
Yield: 30 %

Procedure:
The title compound was prepared in 30% yield from 2-(5-hydroxy-4′-trifluoromethyl-biphenyl-3-yl)-4-methyl-pentanoic acid methyl ester and 3,4,5-trifluorophenylboronic acid under the conditions described in Example 15, step (g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[O:12]([C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22](O)=[O:23])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O.O>[O:12]([C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22]([NH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2)=[O:23])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(O)c1cccc(Oc2ccccc2)c1
Reactant: Nc1ccc2ncccc2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc2ncccc2c1)c1cccc(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 92.7 %

Procedure:
To a solution of 6-aminoquinoline (250 mg, 1.04 mmol) in N,N-dimethylformamide (15 mL) were added 3-phenoxybenzoic acid (371 mg, 1.73 mmol), O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (722 mg, 1.90 mmol) and triethylamine (603 μl, 4.33 mmol), and the solution was stirred for 2 days at room temperature. Water was added to the reaction mixture, which was extracted with ethyl acetate, the organic layer was washed with water, an aqueous solution of saturated sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, and then, concentrated in vacuo. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate), and the title compound (328 mg, 0.964 mmol, 93%) was obtained.
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[O:11][CH3:12])=O.[CH3:13][C:14]1[N:15]=[C:16]([CH2:19][C:20](=O)[CH2:21][CH2:22][CH3:23])[S:17][CH:18]=1.[NH2:25]/[C:26](/[CH3:30])=[CH:27]\[C:28]#[N:29]>C(O)(C)C>[C:7]([C:6]1[CH:9]=[CH:10][C:3]([CH:1]2[C:19]([C:16]3[S:17][CH:18]=[C:14]([CH3:13])[N:15]=3)=[C:20]([CH2:21][CH2:22][CH3:23])[NH:25][C:26]([CH3:30])=[C:27]2[C:28]#[N:29])=[C:4]([O:11][CH3:12])[CH:5]=1)#[N:8]
Reactant: C/C(N)=C/C#N
Reactant: CCCC(=O)Cc1nc(C)cs1
Reactant: COc1cc(C#N)ccc1C=O
Solvent: CC(C)O
Product: CCCC1=C(c2nc(C)cs2)C(c2ccc(C#N)cc2OC)C(C#N)=C(C)N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
100 mg (0.620 mmol) of the compound from example 3A, 114 mg (0.620 mmol) of the compound from example 12A and 51 mg (0.620 mmol) of 3-aminocrotononitrile are dissolved in 4 ml of isopropanol and stirred at the reflux temperature overnight. After cooling to room temperature, the volatile components are removed in a rotary evaporator, and the crude product is purified by preparative HPLC (eluent: acetonitrile/water with 0.1% formic acid, gradient 20:80→95:5). 134 mg (66% of theory) of the title compound are obtained.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[O:19]=[C:20]1[C:25](C(Cl)=O)=[CH:24][CH:23]=[C:22]([CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[O:21]1.[N:34]1[C:43]2[C:38](=[CH:39][C:40]([NH2:44])=[CH:41][CH:42]=2)[CH:37]=[CH:36][CH:35]=1>>[CH3:15][O:14][N:13]=[C:11]1[CH2:12][N:8]([C:6]([C:25]2[C:20](=[O:19])[O:21][C:22]([CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:23][CH:24]=2)=[O:7])[C@H:9]([C:16]([NH:44][C:40]2[CH:39]=[C:38]3[C:43](=[CH:42][CH:41]=2)[N:34]=[CH:35][CH:36]=[CH:37]3)=[O:18])[CH2:10]1
Reactant: CCCCCc1ccc(C(=O)Cl)c(=O)o1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: Nc1ccc2ncccc2c1
Product: CCCCCc1ccc(C(=O)N2CC(=NOC)C[C@H]2C(=O)Nc2ccc3ncccc3c2)c(=O)o1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 2-oxo-6-pentyl-2H-pyran-3-carbonyl chloride, and 6-quinolinamine the title compound was obtained in 57% purity by LC/MS. MS(ESI+): m/z=477.2.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([CH2:7][NH2:8])[CH:4]=[C:3]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:2]=1.[C:15](Cl)(=[O:19])[C:16]([CH3:18])=[CH2:17]>ClCCl>[N:1]1[CH:6]=[C:5]([CH2:7][NH:8][C:15](=[O:19])[C:16]([CH3:18])=[CH2:17])[CH:4]=[C:3]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:2]=1
Reactant: NCc1cncc(-c2cccnc2)c1
Reactant: C=C(C)C(=O)Cl
Solvent: ClCCl
Product: C=C(C)C(=O)NCc1cncc(-c2cccnc2)c1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
To a cooled solution of C-[3,3′]Bipyridinyl-5-yl-methylamine (1.16 g, 6.2 mmol) in dichloromethane (100 mL) was added methacryloyl chloride dropwise. After stirring for 7 h at ambient temperature, the reaction was quenched with 1M NaOH, and extracted with dichloromethane (2×100 mL). The combined organics were washed with sat. NaHCO3, brine, dried with Na2SO4, and evaporated to a yellow oil (1.65 g) which was chromatographed en silica gel (pretreated with 10% triethylamine) using a methanol gradient (0-3%) in dichloromethane to give 0.76 g of clear oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[O:13][CH2:12][CH2:11][O:10]1.C([Li])CCC.CN(C)[CH:21]=[O:22].O>O1CCCC1.CCCCCC>[Cl:1][C:2]1[C:3]([CH:9]2[O:10][CH2:11][CH2:12][O:13]2)=[CH:4][CH:5]=[C:6]([Cl:8])[C:7]=1[CH:21]=[O:22]
Reactant: Clc1ccc(C2OCCO2)c(Cl)c1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: O=Cc1c(Cl)ccc(C2OCCO2)c1Cl
Temperature: -50 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(2,4-dichlorophenyl)-1,3-dioxolane (31.9 g) in tetrahydrofuran (220 ml) was added dropwise 1.6M n-butyllithium in hexane (110 ml) at −60 to −50° C. in a dry ice-acetone bath, and the mixture was stirred at −50° C. After 1 hour, to the reaction mixture was added N,N-dimethylformamide (56.4 ml). After 15 minutes, the mixture was stirred at ambient temperature for 1 hour then water (200 ml) was added thereto. The mixture was extracted with ethyl acetate (100 ml) twice, the organic layer was washed with water 3 times, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by flash silica gel chromatography eluted with n-hexane-ethyl acetate (10:1, V/V) and crystallized with diisopropyl ether to give 2,6-dichloro-3-(1,3-dioxolan-2-yl)benzaldehyde (4.91 g) as colorless crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([OH:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].CI.[C:18](OCC)(=O)C.CCCCCC>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([O:13][CH3:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(C)=O
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CI
Solvent: CN(C)C=O
Product: CO[C@@H]1CCN(C(=O)OC(C)(C)C)C1

Procedure:
(R)-3-Hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (Sigma-Aldrich) (1.04 g, 5.55 mmol) was methylated and purified in a similar way to Preparation 67 using 60% sodium hydride dispersion (267 mg, 6.68 mmol) and methyl iodide (0.5 mL, 8.06 mmol) in DMF (15 ml). δH (CDCl3): 1.50 (9H, s), 1.94-2.02 (2H, m), 3.37 (3H, s), 3.38-3.58 (4H, m), 3.95 (1H, m); Rf 0.47 (ethyl acetate/hexane: 1/1).
Reaction SMILES: CC([Si](C)(C)[O:6][CH2:7][CH2:8][N:9]([CH3:21])[C:10](=[O:20])[C:11]1[CH:16]=[CH:15][C:14](F)=[C:13]([F:18])[C:12]=1F)(C)C.[OH:24][C:25]1[CH:26]=[C:27]([CH:37]=[C:38]([O:40][C@@H:41]([CH3:45])[CH2:42][O:43][CH3:44])[CH:39]=1)[C:28]([NH:30][C:31]1[CH:35]=[CH:34][N:33]([CH3:36])[N:32]=1)=[O:29].C(=O)([O-])[O-].[K+].[K+].O>CC(N(C)C)=O>[F:18][C:13]1[C:12]2[O:6][CH2:7][CH2:8][N:9]([CH3:21])[C:10](=[O:20])[C:11]=2[CH:16]=[CH:15][C:14]=1[O:24][C:25]1[CH:26]=[C:27]([CH:37]=[C:38]([O:40][C@@H:41]([CH3:45])[CH2:42][O:43][CH3:44])[CH:39]=1)[C:28]([NH:30][C:31]1[CH:35]=[CH:34][N:33]([CH3:36])[N:32]=1)=[O:29]
Reactant: COC[C@H](C)Oc1cc(O)cc(C(=O)Nc2ccn(C)n2)c1
Reactant: CN(CCO[Si](C)(C)C(C)(C)C)C(=O)c1ccc(F)c(F)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COC[C@H](C)Oc1cc(Oc2ccc3c(c2F)OCCN(C)C3=O)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 140 °C
Yield: 75.1 %

Procedure:
A suspension of N-(2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}ethyl)-2,3,4-trifluoro-N-methylbenzamide (300 mg, 0.86 mmol), 3-hydroxy-5-[(1S)-2-methoxy-(1-methylethyl)oxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide (278 mg, 0.91 mmol) and potassium carbonate (237 mg, 1.73 mmol) in DMA (20 mL) was heated to 140° C. for 1 hour. The reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (3×50 mL). The combined organic phases were washed with brine (50 mL) and dried (MgSO4), filtered and evaporated to give an orange oil. This was purified via column chromatography on silica, eluting with 50-100% ethyl acetate in isohexane, to give the desired product as a colourless oil (322 mg). 1H NMR δ (CDCl3): 1.25 (d, 3H), 2.77 (s, 3H), 3.33 (s, 3H), 3.44 (dd, 1H), 3.50 (dd, 1H), 3.71 (s, 3H), 3.74 (t, 2H), 4.25 (t, 2H), 4.49-4.56 (m, 1H), 6.71 (d, 1H), 6.73 (t, 1H), 6.75 (dd, 1H), 7.04 (t, 1H), 7.20-7.20 (m, 1H), 7.22 (d, 1H), 7.47 (dd, 1H), 8.68 (s, 1H); m/z 499 (M+H)+
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[C:17]([NH:34][C:35]4[CH:44]=[C:43]5[C:38]([CH:39]=[CH:40][CH:41]=[N:42]5)=[CH:37][CH:36]=4)=[N:18][CH:19]=[C:20]([C@H:22]([N:24]4[CH2:29][CH2:28][N:27]([S:30]([CH3:33])(=[O:32])=[O:31])[CH2:26][CH2:25]4)[CH3:23])[CH:21]=3)[N:10]=2)=CC=1.FC(F)(F)S(O)(=O)=O.[C:64]([OH:70])([C:66]([F:69])([F:68])[F:67])=[O:65]>>[F:67][C:66]([F:69])([F:68])[C:64]([OH:70])=[O:65].[NH2:8][C:9]1[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]2[C:17]([NH:34][C:35]3[CH:44]=[C:43]4[C:38]([CH:39]=[CH:40][CH:41]=[N:42]4)=[CH:37][CH:36]=3)=[N:18][CH:19]=[C:20]([C@H:22]([N:24]3[CH2:25][CH2:26][N:27]([S:30]([CH3:33])(=[O:31])=[O:32])[CH2:28][CH2:29]3)[CH3:23])[CH:21]=2)[N:10]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc([C@@H](C)N4CCN(S(C)(=O)=O)CC4)cnc3Nc3ccc4cccnc4c3)n2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(N)nc(-c2cc([C@@H](C)N3CCN(S(C)(=O)=O)CC3)cnc2Nc2ccc3cccnc3c2)n1
Temperature: 25 °C
Yield: 36.5 %

Procedure:
A brown solution of (R)—N-(3-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-5-(1-(4-(methylsulfonyl)piperazin-1-yl)ethyl)pyridin-2-yl)quinolin-7-amine (170.8 mg, 0.225 mmol) and trifluoromethanesulfonic acid (0.2 mL, 2.252 mmol) (10% v/v with TFA) in TFA (2.0 mL) was stirred at 75° C. for 1.5 h. The reaction mixture was subsequently cooled to 25° C. and concentrated in vacuo. The residue was taken up in CH2Cl2 (50 mL), and the resulting solution was washed with saturated aqueous sodium bicarbonate (40 mL). The organic layer was separated, and the aqueous layer was extracted with CH2Cl2 (2×30 mL). All organic layers were then combined, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was taken up in DMSO (2.0 mL) and purified by rpHPLC (Phenomenex Luna 5 μm C18, 30×150 mm, 45 mL/min, 10 to 100% CH3CN/H2O (plus 0.1% TFA, both solvents)) to provide (R)—N-(3-(4-amino-6-methyl-1,3,5-triazin-2-yl)-5-(1-(4-(methylsulfonyl)piperazin-1-yl)ethyl)pyridin-2-yl)quinolin-7-amine 2,2,2-trifluoroacetate (52.0 mg, 0.082 mmol, 36.5% yield) as a yellow-orange solid. 1H NMR (400 MHz, d4-MeOH) δ 9.52 (d, J=1.8 Hz, 1H), 9.18 (d, J=2.5 Hz, 1H), 8.99 (d, J=8.2 Hz, 1H), 8.96 (dd, J=5.6, 1.3Hz, 1H), 8.68 (d, J=2.5 Hz, 1H), 8.25 (d, J=9.2 Hz, 1H), 8.04 (dd, J=9.0, 2.0 Hz, 1H), 7.83 (dd, J=8.0, 5.7 Hz, 1H), 4.70 (q, J=7.0 Hz, 1H), 3.55 (br. s., 4H), 2.94 (s, 3H), 2.65 (s, 4H), 2.58 (s, 3H), 1.89 (d, J=6.8 Hz, 3H). 19F NMR (376 MHz, d4-MeOH) δ −77.36 (s, 3F). m/z (ESI, +ve) 520.2 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[C@@H:5]([C:14]([OH:16])=O)[CH2:4][CH2:3]1.[NH2:17][CH:18]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH:19]([OH:23])[C:20]([NH2:22])=[O:21].O[NH-].O=[N-].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>>[NH2:22][C:20](=[O:21])[C:19](=[O:23])[CH:18]([NH:17][C:14]([C@H:5]1[CH2:4][CH2:3][C:2](=[O:1])[N:6]1[CH2:7][C:8]1[CH:9]=[CH:10][N:11]=[CH:12][CH:13]=1)=[O:16])[CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C(O)[C@H]1CCC(=O)N1Cc1ccncc1
Reactant: NC(=O)C(O)C(N)Cc1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [N-]=O
Agent: [NH-]O
Product: NC(=O)C(=O)C(Cc1ccccc1)NC(=O)[C@H]1CCC(=O)N1Cc1ccncc1

Procedure:
Coupling of (R)-5-oxo-1-pyridin-4-ylmethyl-pyrrolidine-2-carboxylic acid with 3-amino-2-hydroxy-4-phenylbutanamide and oxidation of the resulting hydroxyamide intermediate to the corresponding ketoamide using Dess Martin reagent.
Reaction SMILES: CC1(C)[O:6][C:5](=[CH:7][C:8]([N:10]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[S:20]([CH3:22])=[O:21])[CH3:11])=[O:9])[C:4](=[O:23])O1.[CH2:25]=O.[N:27]1([CH2:33][CH2:34][NH2:35])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[F:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][N:10]([CH3:11])[C:8]([C:7]2[CH2:25][N:35]([CH2:34][CH2:33][N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[C:4](=[O:23])[C:5]=2[OH:6])=[O:9])=[C:14]([S:20]([CH3:22])=[O:21])[CH:15]=1
Reactant: C=O
Reactant: NCCN1CCOCC1
Reactant: CN(Cc1ccc(F)cc1S(C)=O)C(=O)C=C1OC(C)(C)OC1=O
Product: CN(Cc1ccc(F)cc1S(C)=O)C(=O)C1=C(O)C(=O)N(CCN2CCOCC2)C1
Yield: 88 %

Procedure:
2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(4-fluoro-2-methanesulfinyl-benzyl)-N-methyl-acetamide was reacted with paraformaldehyde and 2-morpholin-4-yl-ethylamine as described in Method 44 B to give the title compound as a yellow solid (0.04 g, 88% yield). 1HNMR (300 MHz, MeOD) δ: 7.72 (1H, dd, J=8.42, 2.56 Hz), 7.49 (1H, dd, J=8.79, 5.13 Hz), 7.32–7.26 (1H, m), 4.19 (2H, s), 4.09–3.46 (10H, m), 3.30–3.21 (2H, m), 3.12 (3H, s), 2.81 (3H, s).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:9]([N:11]3[CH:16]4[CH2:17][CH2:18][CH:12]3[CH2:13][C:14](=O)[CH2:15]4)=[N:8][CH:7]=[N:6][C:5]=2[S:4][CH:3]=1.[CH:20]1([NH2:24])[CH2:23][CH2:22][CH2:21]1.C(O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:10]2[C:9]([N:11]3[CH:16]4[CH2:17][CH2:18][CH:12]3[CH2:13][CH:14]([NH:24][CH:20]3[CH2:23][CH2:22][CH2:21]3)[CH2:15]4)=[N:8][CH:7]=[N:6][C:5]=2[S:4][CH:3]=1
Reactant: O=C1CC2CCC(C1)N2c1ncnc2scc(Br)c12
Reactant: NC1CCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Brc1csc2ncnc(N3C4CCC3CC(NC3CCC3)C4)c12
Temperature: 30 °C
Yield: 89.6 %

Procedure:
8-(5-Bromothieno[2,3-d]pyrimidin-4-yl)-8-azabicyclo[3.2.1]octan-3-one (1.5 g, 4.43 mmol) in toluene (60 mL) was treated with cyclobutylamine (3.145 g, 44.3 mmol) and heated with stirring to reflux for 2 h. Ethanol (100 mL) and sodium triacetoxyborohydride (9.347 g, 44.3 mmol) were added and the reaction stirred and warmed at 30° C. over 3 days. The reaction was then concentrated in vacuum to a gum, diluted with ethyl acetate (100 mL) and saturated sodium hydrogen carbonate solution (50 mL) and shaken. The ethyl acetate layer was then separated, dried over sodium sulphate and concentrated in vacuum to give 8-(5-bromothieno[2,3-d]pyrimidin-4-yl)-N-cyclobutyl-8-azabicyclo[3.2.1]octan-3-amine as a yellow solid (1.799 g, 3.97 mmol, 89%). 1H NMR (CDCl3) δ: 1.5 (3H, d, J=12 Hz), 1.65 (3H, br s), 1.93 (2H, br s), 2.1 (2H, d, J=6 Hz), 2.22 (2H, m), 2.4 (2H, m), 3.0 (1H, br s), 3.3 (1H, m), 4.63 (2H, br s), 7.3 (1H, s), 8.45 (1H, s).
Reaction SMILES: Cl.[CH3:2][NH:3][CH2:4][C:5]([NH:7][C:8]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:9]=1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:11])=[O:6].C1(C)C(C)=CC=CC=1.Cl[CH2:32][C:33]([OH:35])=[O:34]>C(N(CC)CC)C>[ClH:22].[C:33]([CH2:32][N:3]([CH3:2])[CH2:4][C:5]([NH:7][C:8]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:9]=1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:11])=[O:6])([OH:35])=[O:34]
Reactant: O=C(O)CCl
Reactant: CNCC(=O)Nc1ccc(Cl)cc1C(=O)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1C
Product: CN(CC(=O)O)CC(=O)Nc1ccc(Cl)cc1C(=O)c1ccccc1
Yield: 104 %

Procedure:
4.6 g of 2-(methylamino-acetamido)-5-chlorobenzophenone hydrochloride were heated in 100 mls. of dry xylene with 3 g of triethylamine and 1.9 g of chloracetic acid for 8 hours under reflux whilst stirring. After cooling, the precipitated triethylamine hydrochloride was filtered off and the filtrate was shaken 3 times with 100 mls. of water each time. After drying over potassium carbonate and filtering, it was concentrated in vacuo, the oily crude base obtained being dissolved in 100 mls. of dry ether and filtered again. By passing in dry hydrogen chloride gas, filtering under suction and drying in a vacuum desiccator, 2.8 g (71% of theory) of 2-(4-carboxy-3-methyl-3-aza-butyramido)-5-chlorobenzophenone hydrochloride were obtained with a melting point of 162°-164°.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[CH3:12].C(N(CC)CC)C.[C:20](OC(=O)C)(=[O:22])[CH3:21].O>ClCCl>[C:20]([O:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[CH3:12])(=[O:22])[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc(Cl)cc1CCCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(=O)OCCCc1cc(Cl)ccc1C
Reaction time: 2 h
Yield: 65.8 %

Procedure:
To a solution of 2-(3-hydroxypropyl)-4-chloro-toluene (6.2 g, 33.5 mmol) and triethylamine (9.34 mL, 67 mmol) in dichloromethane (25 mL) was added acetic anhydride (5.1 mL, 50.3 mmol) at room temperature. The mixture was stirred for 2 h and concentrated in vacuo. The residue was diluted with aq. KHSO4 and extracted with AcOEt. The extracts were dried and concentrated. The residue was dissolved in dichloromethane (50 mL). NO2 +BF4- (5.77 g, 36.85 mmol) was added at 0° C. The mixture was stirred for 30 min at 0° C. and poured into water. The mixture was extracted with AcOEt and the extracts was dried and concentrated. The residue was purified by silica gel column chromatography with 5:1 hexane/AcOEt to give 5.0 g of the title compound: 1H NMR (CDCl3) δ7.63 (bs, 1H), 7.36 (bs, 1H), 4.13 (t, 2H, J=7.2 Hz), 2.78 (t, 2H, J=7.2 Hz), 2.41 (s, 3H), 2.09 (s, 3H), 1.89~2.01 (m, 2H).